Natural killer (NK) cells probably function as an early defense line against viruses, due to their ability to kill virus-infected cells without resorting to clonal proliferation of memory cells. NK cells are also capable of killing tumor cells. In both cases the killing is major histocompatibility complex (MHC) unrestricted. NK cells exhibit spontaneous activity but they are positively regulated by interferon (IFN) or indirectly by such IFN-inducers as viruses, bacterial products, poly (rl):(rC), and mitogens. Interleukin-2 (IL-2) has the ability to enhance NK activity in addition to its ability to generate lymphokine-activated killer (LAK) cell activity. Recently, it was documented that other cytokines (e.g., IL-1, tumor necrosis factor (TNF), IL-6, and IL-12) are also involved in induction or enhancement of the cytotoxic activity of NK cells. Besides their "positive" regulation of NK activity, cytokines (in some cases the same cytokines) often act as "negative signals" for NK-mediated cytotoxicity. If NK susceptible target cells are exposed to IFN prior to NK cells, their sensitivity to NK activity is often markedly diminished. The mechanism by which IFNs (IFN-alpha, -beta and -gamma) affect the sensitivity of target cells to NK activity remains unknown, but it is clear that this function is not shared by other cell-mediated killing processes. The protective effect induced by IFN against NK activity is dependent on new mRNA and protein synthesis and can be abolished when target cells are incubated with combination of IFN and metabolic inhibitors or by chemotherapeutic purine or pyrimidine analogs. Class I MHC antigens have a central role in cell to cell interactions in the immune system. Because IFN has the ability to induce/increase class I MHC antigen expression, it has been suggested that class I MHC antigens act as "negative signals" of NK-mediated cytotoxicity. Although many studies support this hypothesis, others present evidence for a lack of involvement of class I MHC antigens in mediating sensitivity to NK activity. Other cytokines have been tested for their ability to affect the sensitivity of target cells to NK activity, as well as their ability to enhance the cytotoxic activity of NK effector cells. Lymphotoxin (TNF-beta) increases target cell susceptibility to NK activity. On the other hand, IL-1, IL-2, IL-6, and TNF reduce the sensitivity of target cells to NK lysis, at least in some systems.(ABSTRACT TRUNCATED AT 400 WORDS)